Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references may be found at the end of this application, preceding the claims.
The peptide neurotransmitter neuropeptide Y (NPY) is a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system (Dumont et al., 1992). The family includes the pancreatic polypeptide (PP), synthesized primarily by endocrine cells in the pancreas; peptide YY (PYY), synthesized primarily by endocrine cells in the gut; and NPY, synthesized primarily in neurons (Michel, 1991; Dumont et al., 1992; Wahlestedt and Reis, 1993). All pancreatic polypeptide family members share a compact structure involving a xe2x80x9cPP-foldxe2x80x9d and a conserved C-terminal hexapeptide ending in Tyr36 (or Y36 in the single letter code). The striking conservation of Y36 has prompted the reference to the pancreatic polypeptides"" receptors as xe2x80x9cY-typexe2x80x9d receptors (Wahlestedt et al., 1987), all of which are proposed to function as seven transmembrane-spanning G protein-coupled receptors (Dumont et al., 1992).
NPY and its relatives elicit a broad range of physiological effects through activation of at least five G protein-coupled receptor subtypes known as Y1, Y2, Y3, Y4 (or PP), and the xe2x80x9catypical Y1xe2x80x9d. While the Y1, Y2, Y3, and Y4 (or PP) receptors were each described previously in both radioligand binding and functional assays, the xe2x80x9catypical Y1xe2x80x9d receptor is unique in that its classification is based solely on feeding behavior induced by various peptides including NPY.
The role of NPY in normal and abnormal eating behavior, and the ability to interfere with NPY-dependent pathways as a means to appetite and weight control, are areas of great interest in pharmacological and pharmaceutical research (Sahu and Kalra, 1993; Dryden et al., 1994). NPY is considered to be the most powerful stimulant of feeding behavior yet described (Clark et al., 1984; Levine and Morley, 1984; Stanley and Leibowitz, 1984). The stimulation of feeding behavior by NPY is thought to occur primarily through activation of the hypothalamic xe2x80x9catypical Y1xe2x80x9d receptor. For example, direct injection of NPY into the hypothalamus of satiated rats can increase food intake up to 10-fold over a 4-hour period (Stanley et al., 1992). Similar studies using other peptides has resulted in a pharmacologic profile for the xe2x80x9catypical Y1xe2x80x9d receptor according to the rank order of potencies of peptides in stimulating feeding behavior as follows: NPY2-36 NPYxcx9cPYYxcx9c[Leu31,Pro34]NPY greater than NPY13-36 (Kalra et al., 1991; Stanley et al., 1992). The profile is similar to that of a Y1-like receptor except for the anomalous ability of NPY2-36 to stimulate food intake with potency equivalent or better than that of NPY. A subsequent report in J. Med. Chem. by Balasubramaniam and co-workers (1994) showed that feeding can be regulated by [D-Trp32]NPY. While this peptide was presented as an NPY antagonist, the published data at least in part support a stimulatory effect of [D-Trp32]NPY on feeding. In contrast to other NPY receptor subtypes, the xe2x80x9cfeedingxe2x80x9d receptor has never been characterized for peptide binding affinity in radioligand binding assays.
This problem has been addressed by cloning rat and human cDNAs which encode a single receptor protein, referred to herein as Y5, whose pharmacologic profile links it to the xe2x80x9catypical Y1xe2x80x9d receptor. The identification and characterization of a single molecular entity which explains the xe2x80x9catypical Y1xe2x80x9d receptor allows the design of selective drugs which modulate feeding behavior (WO 96/16542). It is important to note, though, that any credible means of studying or modifying NPY-dependent feeding behavior must necessarily be highly selective, as NPY interacts with multiple receptor subtypes, as noted above (Dumont et al., 1992).
As used in this invention, the term xe2x80x9cantagonistxe2x80x9d refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific but by no means limiting examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase, and inositol phospholipid hydrolysis. Conversely, the term xe2x80x9cagonistxe2x80x9d refers to a compound which binds to, and increases the activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
In order to test compounds for selective binding to the human Y5 receptor the cloned cDNAs encoding both the human and rat Y2 and Y4 (or PP) receptors have been used. The human and rat Y5 receptors are described in coassigned U.S. Pat. No. 5,602,024 and in PCT International Application US95/15646, published Jun. 6, 1996, as WO 96/16542, the contents of which are hereby incorporated by reference into this application. The human and rat Y2 receptors are described in coassigned U.S. Pat. No. 5,545,549 and in PCT International Application US95/01469, published Aug. 10, 1995, as WO 95/21245, the contents of which are hereby incorporated by reference into this application. The human and rat Y4 receptors are described in coassigned U.S. Pat. No. 5,516,653 and in PCT International Application PCT/US94/14436, published Jul. 6, 1995, as WO 95/17906, the contents of which are hereby incorporated by reference into this application. The Y1 receptor has been cloned from a variety of species including human, rat and mouse (Larhammar et al., 1992; Herzog et al., 1992; Eva et al., 1990; Eva et al., 1992).
Using the NPY-Y5-selective antagonist CGP 71683A, it was demonstrated recently that food intake in free-feeding and energy-derived lean rats is mediated by the Y5 receptor (Criscione et al., 1998). CGP 71683A has high affinity for the cloned rat NPY-Y5 receptor subtype, but 1,000-fold lower affinity for the cloned rat NPY-Y1, Y2, and Y4 receptors. Examples of additional NPY-Y5-selective compounds are disclosed in WO 97/20823, WO 98/35957, and WO 98/35944.
In one embodiment of this invention the synthesis of novel triazine compounds which bind selectively to the cloned human Y5 receptor, compared to the other cloned human NPY receptors, and inhibit the activation of the cloned human Y5 receptor as measured in in vitro assays is disclosed. The in vitro receptor binding and activation assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single Y-type receptor.
In addition, the compounds of the present invention may be used to treat abnormal conditions such as feeding disorders (obesity and bulimia nervosa), sexual/reproductive disorders, depression, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of a Y5 receptor may be beneficial.
This invention provides a compound having the structure 
wherein R1 is F; Cl; Br; I; NR3R4; or phenyl or heteroaryl; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
wherein R2 is NR3R4;
wherein R3 is independently H; xe2x80x94(CH2)uYR5; xe2x80x94(CH2)tC(Y)NR5R6; xe2x80x94(CH2)uNR5C(Y)R5; xe2x80x94(CH2)tC(Y)R7; xe2x80x94(CH2)tCO2R5; xe2x80x94(CH2)uNR5R6; xe2x80x94(CH2)uCN; xe2x80x94C(Y)R5; xe2x80x94C(Y)NR5R6; xe2x80x94CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
wherein R4 is independently H; xe2x80x94(CH2)uYR5; xe2x80x94(CH2)tC(Y)NR5R6; xe2x80x94(CH2)uNR5C(Y)R5; xe2x80x94(CH2)tC(Y)R7; xe2x80x94(CH2)tCO2R5; xe2x80x94(CH2)uNR5R6; xe2x80x94(CH2)uCN; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
or R3 and R4 taken together with the nitrogen atom to which they are attached are 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl, wherein the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl is substituted with one or more of F, xe2x80x94CN, xe2x80x94(CH2)nNR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, a C3-C7 cycloalkyl or cycloalkenyl, or phenyl or heteroaryl; wherein if xe2x80x94(CH2)nNR5R6, xe2x80x94(CH2)nYR5, or xe2x80x94(CH2)nNR5C(Y)R5 are in the 2-position, then n is not 0; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
or R3 and R4 taken together with the nitrogen atom to which they are attached are morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl, wherein the morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl is substituted with one or more straight chained or branched C1-C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl or [1,4]diazepanyl ring is substituted with xe2x80x94(CH2)uYR5; xe2x80x94(CH2)tC(Y)NR5R6; xe2x80x94(CH2)uNR5C(Y)R5; xe2x80x94(CH2)tC(Y)R7; xe2x80x94(CH2)tCO2R5; xe2x80x94(CH2)uNR5R6; xe2x80x94(CH2)uCN; xe2x80x94C(Y)R5; xe2x80x94C(Y)NR5R6; xe2x80x94CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
wherein each of R5, R6 and R7 is independently H; or straight chained or branched C1-C7 alkyl;
wherein each n is independently an integer from 0 to 6 inclusive;
wherein each t is independently an integer from 1 to 4 inclusive;
wherein each u is independently an integer from 2 to 4 inclusive;
wherein Y is O or S;
wherein R8 is 
provided that if R8 contains a piperidinyl group and m is O, then the compound is not an xcex1-aminal-containing compound;
wherein each of R9 and R10 is independently H; straight chained or branched C1-C4 alkyl;
wherein R11 is H or 
wherein R12 is H;
wherein R13 is independently H; xe2x80x94(CH2)uYR5; xe2x80x94(CH2)tC(Y)NR5R6; xe2x80x94(CH2)uNR5C(Y)R5; xe2x80x94(CH2)tC(Y)R7; xe2x80x94(CH2)tCO2R5; xe2x80x94(CH2)uNR5R6; xe2x80x94(CH2)uCN; xe2x80x94C(Y)R5; xe2x80x94C(Y)NR5R6; xe2x80x94CO2R5; straight chained or branched C1-C7 alkyl; C1-C7 alkyl substituted with one or more F or Cl; C3-C7 cycloalkyl-C1-C7 alkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C (Y) R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
or R12 and R13 together with the amide linkage to which they are attached are pyrrolidinonyl or piperidonyl;
wherein R14 is H; straight chained or branched C1-C7 alkyl; F; or xe2x80x94(CH2)nOR5;
wherein R15 is H, straight chained or branched C1-C7 alkyl, or F;
wherein R16 is NR3R4, unsubstituted straight chained or branched C2-C7 alkyl, substituted straight chained or branched C1-C7 alkyl, wherein the C1-C7 alkyl may be substituted with one or more of F, Cl, xe2x80x94CN, xe2x80x94NR5R6, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nOCF3, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl, or C3-C7 cycloalkyl or cycloalkenyl, phenyl, heteroaryl, or C1-C7 phenylalkyl, wherein the phenyl, heteroaryl, or C1-C7 phenylalkyl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94(CH2)nNR5C(Y)R5, xe2x80x94SO2R5, xe2x80x94(CH2)nC(Y)R7, xe2x80x94(CH2)nYR5, xe2x80x94(CH2)nC(Y)NR5R6, xe2x80x94(CH2)nCO2R5, xe2x80x94(CH2)nSO2NR5R6, ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; quinolinyl, 1-naphthyl, 2-naphthyl, or 2,1,3-benzothiadiazolyl; with the provisos that when R1 is F, Cl, Br, or I, then R16 is 1-naphthyl; and when R1 and R2 are morpholinyl, then R16 is not NR3R4;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each s is independently an integer from 1 to 6 inclusive;
wherein each p is independently an integer from 0 to 2 inclusive;
wherein each q is independently an integer from 1 to 2 inclusive;
wherein each r is independently an integer from 1 to 2 inclusive;
wherein X is N or C;
or a pharmaceutically acceptable salt thereof.